Method for Reducing Gastrointestinal Toxicity Due to the Administration of Tegafur

Abstract

This invention provides a method for potentiating the antitumor effect of tegafur and reducing the gastrointestinal toxicity. The method comprises administering a composition containing tegafur, a DPD inhibitor and oxonic acid or a pharmaceutically acceptable salt thereof, to a patient under fasting conditions.

1 . A method for potentiating the antitumor effect of tegafur while reducing gastrointestinal toxicity in a patient in need of such treatment, comprising simultaneously administering to said patient (A) a therapeutically effective amount of tegafur, (B) a dihydropyrimidine dehydrogenase inhibitor in an amount effective for potentiating the antitumor effect and (C) oxonic acid or a pharmaceutically acceptable salt thereof in an amount effective for suppressing gastrointestinal toxicity, under fasting conditions. 
     
     
         2 . The method according to  claim 1 , wherein the administrations of the composition are twice over the course of a day, under fasting conditions. 
     
     
         3 . The method according to  claim 1 , wherein said dihydropyrimidine dehydrogenase inhibitor is 2,4-dihydroxy-5-chloropyridine. 
     
     
         4 . The method according to  claim 1 , wherein the two administrations of the composition are separated by 6-12 hours. 
     
     
         5 . The method according to  claim 1 , wherein the fasting conditions occur at least one hour before or after a meal. 
     
     
         6 . The method according to  claim 5 , wherein the fasting conditions occur at least one hour before a meal. 
     
     
         7 . The method according to  claim 3 , wherein the 2,4-dihydroxy-5-chloropyridine (B) and the oxonic acid or a pharmaceutically acceptable salt thereof (C) are used in a molar ratio of (B):(C)=0.4:1. 
     
     
         8 . The method according to  claim 1 , wherein the pharmaceutically acceptable salt is potassium oxonate. 
     
     
         9 . The method according to  claim 3 , wherein said tegafur, said 2,4-dihydroxy-5-chloropyridine, and said oxonic acid or a pharmaceutically acceptable salt thereof are used in a molar ratio of (tegafur):(2,4-dihydroxy-5-chloropyridine):(oxonic acid or a pharmaceutically acceptable salt thereof =1:0.4:1. 
     
     
         10 . The method according to  claim 1 , wherein said tegafur is administered at a dose of between 20 mg/m 2  to 45 mg/m 2  twice daily. 
     
     
         11 . The method according to  claim 1 , further comprising administering a chemotherapy agent selected from the group consisting of cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, docetaxel, doxorubicin, epirubicin, etoposide, methotrexate, mitomycin, gemcitabine, carboplatin, gefitinib, pemetrexed, Avastin, Cetuximab and paclitaxel. 
     
     
         12 . The method according to  claim 11 , wherein said chemotherapy agent is cisplatin administered intravenously. 
     
     
         13 . The method according to  claim 12 , wherein said cisplatin is administered at a dose between 50-80 mg/m 2  daily. 
     
     
         14 . A method for treating cancer in a mammal wherein the cancer is susceptible to 5-fluorouracil therapy, the method comprising simultaneously administering to the mammal a therapeutically effective amount of tegafur, 2,4-dihydroxy-5-chloropyridine in an amount effective for potentiating the antitumor effect of tegafur, and oxonic acid or a pharmaceutically acceptable salt thereof in an amount effective for suppressing gastrointestinal toxicity, under fasting conditions. 
     
     
         15 . The method according to  claim 14 , wherein the administrations are twice over the course of a day, under fasting conditions. 
     
     
         16 . The method according to  claim 14 , wherein the two administrations are separated by 6-12 hours. 
     
     
         17 . The method according to  claim 14 , wherein the molar ratio of (tegafur):(2,4-dihydroxy-5-chloropyridine):(oxonic acid or a pharmaceutically acceptable salt thereof) is preferably 1:0.4:1. 
     
     
         18 . The method according to  claim 14 , wherein said tegafur is administered in a dose of between 20 mg/m 2  to 45 mg/m 2  twice daily. 
     
     
         19 . The method according to  claim 14 , wherein said fasting conditions occur at least one hour before or after a meal. 
     
     
         20 . The method according to  claim 14 , wherein said fasting conditions occur one hour before a meal. 
     
     
         21 . A method for inhibiting inflammation and gastrointestinal toxicity caused by the administration of tegafur, comprising administering oxonic acid or a pharmaceutically acceptable salt thereof in an amount effective for suppressing gastrointestinal toxicity, simultaneously with said tegafur to a patient in need of such treatment, wherein said tegafur and oxonic acid or a pharmaceutically acceptable salt thereof are administered under fasting conditions. 
     
     
         22 . The method according to  claim 21 , wherein the administrations of the composition are twice a day under fasting conditions. 
     
     
         23 . The method according to  claim 21 , further comprising simultaneously administering a dihydropyrimidine dehydrogenase inhibitor in an amount effective for potentiating the antitumor effect of tegafur. 
     
     
         24 . A method for decreasing the breakdown of oxonic acid in the gastrointestinal tract of a patient undergoing treatment with tegafur, comprising administering oxonic acid simultaneously with said tegafur to said patient under fasting conditions. 
     
     
         25 . The method according to  claim 24 , wherein the administrations of tegafur simultaneously with oxonic acid are twice daily under fasting conditions. 
     
     
         26 . The method according to  claim 24 , further comprising simultaneously administering a dihydropyrimidine dehydrogenase inhibitor in an amount effective for potentiating the antitumor effect of tegafur. 
     
     
         27 . The method according to  claim 25 , wherein said dihydropyrimidine dehydrogenase inhibitor is 2,4-dihydroxy-5-chloropyridine. 
     
     
         28 . The method according to  claim 25 , wherein said fasting conditions occur at least one hour before or after a meal. 
     
     
         29 . A kit for treating cancer in a mammal, comprising tegafur, 2,4-dihydroxy-5-chloropyridine, oxonic acid or a pharmaceutically acceptable salt thereof in dosages suitable for administration twice a day, and optionally comprising an anti-tumor agent selected from the group consisting of cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, docetaxel, doxorubicin, epirubicin, etoposide, methotrexate, mitomycin, gemcitabine, carboplatin, gefitinib, pemetrexed, Avastin, Cetuximab and paclitaxel, the kit further comprising an indicator that reminds that said tegafur, said 2,4-dihydroxy-5-chloropyridine, and said oxonic acid or a pharmaceutically acceptable salt thereof should be administered under fasting conditions. 
     
     
         30 . A pharmaceutical composition for potentiating the antitumor effect of tegafur while reducing gastrointestinal toxicity in a patient in need of such treatment, comprising (A) a therapeutically effective amount of tegafur, (B) a dihydropyrimidine dehydrogenase inhibitor in an amount effective for potentiating the antitumor effect and (C) oxonic acid or a pharmaceutically acceptable salt thereof in an amount effective for suppressing gastrointestinal toxicity, and optionally an additional anti-tumor agent selected from the group consisting of cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, docetaxel, doxorubicin, epirubicin, etoposide, methotrexate, mitomycin, gemcitabine, carboplatin, gefitinib, pemetrexed, Avastin, Cetuximab and paclitaxel, the pharmaceutical composition being contained in a package that comprises an indicator that reminds the patient that the pharmaceutical composition should be administered under fasting conditions.